The major histocompatibility complex (Mhc) is a family of genes whose function is to provide context for the recognition of foreign antigens by T lymphocytes. One of the distinguishing features of the Mhc is its polymorphism, that is, the occurrence in natural populations of large numbers of alleles at some of the Mhc loci, all at appreciable frequencies. The overall goal of the proposed research is to determine how the Mhc polymorphism arises and to elucidate its biological significance. The proposed project will attempt to answer questions such as: How fast do Mhc genes diversify? What mechanisms are involved in this diversification? What is the origin of the polymorphic Mhc loci? What role does the t complex (a set of linked loci affecting differentiation) play in the generation of the Mhc polymorphism? To what degree does the polymorphism correlate with the adaptiveness of a species to its environment? Answers to these questions will be sought by extracting DNA from populations of wild mice and mole-rats, and studying it using methods of molecular biology. The study should contribute to three areas of human knowledge. In immunology, the results might provide a clue to understanding why T lymphocytes need to recognize nonself in the context of self. In general biology, the study of polymorphism should provide information on how a species copes with its environment, in particular the invading parasites. In evolutionary biology, the data should shed light on how speciation begins. Although the studies will be carried out on rodents, it is hoped that they will be directly applicable to humans who, like mice, possess a highly polymorphic Mhc.